We performed a double-blind placebo-controlled trial of oral acyclovir in the treatment of first episodes of genital herpes simplex virus infections in 48 young adults (31 women and 17 men). Subjects were randomized to receive either placebo or acyclovir (200 mg per dose) five times daily for 10 days; they were examined on at least eight visits until healed and at monthly visits thereafter. Acyclovir treatment, as compared with placebo, significantly reduced virus shedding, new lesion formation after 48 hours, and the duration of genital lesions in both men and women. The total duration and severity of clinical symptoms (such as pain, adenopathy, dysuria, and malaise) were significantly reduced by acyclovir in both men and women by the third and fourth day, respectively (P less than or equal to 0.025), as compared with placebo. No toxicity was observed. Recurrence rates have so far been similar in placebo and acyclovir recipients. Oral acyclovir treatment of first-episode genital herpes simplex virus infections is clinically effective, but it does not seem to prevent virus latency or associated recurrent disease.